Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development

Zou, Yong-Rui; Kottmann, Andreas H.; Kuroda, Masahiko; Taniuchi, Ichiro; Littman, Dan R.

doi:10.1038/31269

Cited by 2,305 publications

(1,843 citation statements)

References 30 publications

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“…The functions of CXCR4 have not yet been fully understood, but it appears that it mediates a large variety of functions including leukocyte development and trafficking, HIV-infection, correct foetal vascularisation and CNS development and possibly cell division, tumourigenesis and growth (Tachibana et al, 1998;Zou et al, 1998;Gabuzda and Wang, 1999). Rempel et al (2000) observed a tumour grade-dependent surge of CXCR4 mRNA levels in glioblastoma multiforme and that this receptor is mainly expressed in regions of angiogenesis and degenerative, necrotic, and microcystic changes rather than in sections of rapid cell proliferation.…”

Section: Molecular and Cellular Pathologymentioning

confidence: 99%

CXCR4/CXCL12 expression and signalling in kidney cancer

et al. 2002

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CXCL12 (SDF-1), a CXC-chemokine, and its specific receptor, CXCR4, have recently been shown to be involved in tumourgenesis, proliferation and angiogenesis. Therefore, we analysed CXCL12α/CXCR4 expression and function in four human kidney cancer cell lines (A-498, CAKI-1, CAKI-2, HA-7), 10 freshly harvested human tumour samples and corresponding normal kidney tissue. While none of the analysed tumour cell lines expressed CXCL12α, A-498 cells were found to express CXCR4. More importantly, real-time RT–PCR analysis of 10 tumour samples and respective adjacent normal kidney tissue disclosed a distinct and divergent downregulation of CXCL12α and upregulation of CXCR4 in primary tumour tissue. To prove that the CXCR4 protein is functionally active, rhCXCL12α was investigated for its ability to induce changes of intracellular calcium levels in A-498 cells. Moreover, we used cDNA expression arrays to evaluate the biological influence of CXCL12α. Comparing gene expression profiles in rhCXCL12α stimulated vs unstimulated A-498 kidney cancer cells revealed specific regulation of 31 out of 1176 genes tested on a selected human cancer array, with a prominent stimulation of genes involved in cell-cycle regulation and apoptosis. The genetic changes reported here should provide new insights into the developmental paths leading to tumour progression and may also aid the design of new approaches to therapeutic intervention. British Journal of Cancer (2002) 86 , 1250–1256. DOI: 10.1038/sj/bjc/6600221 www.bjcancer.com © 2002 Cancer Research UK

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Section: Molecular and Cellular Pathologymentioning

confidence: 99%

CXCR4/CXCL12 expression and signalling in kidney cancer

et al. 2002

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“…Stem cells are believed to reside in close proximity to the endosteal surface of the bone, where osteoblasts are also located 21,22 . Interactions between SDF-1, produced by the osteoblasts 21 , and its receptor, CXCR4, expressed by the stem/progenitor cells 23,24 , is thought to play a major role in stem cell trafficking in embryogenesis 17,24 and in maintaining the stem cells within their niche in the marrow 25,26 . A great deal of evidence indicates that alterations in SDF-1 concentrations in marrow and blood result in stem/progenitor cell mobilization.…”

Section: Introductionmentioning

confidence: 99%

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Migliaccio

Martelli

Verrucci

et al. 2008

Experimental Hematology

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Objective-To assess whether alterations in the SDF-1/CXCR4 occur in patients with primary myelofibrosis (PMF) and in Gata1 low mice, an animal model for myelofibrosis, and whether these abnormalities might account for increased stem/progenitor cell trafficking.Materials and Methods-In the mouse, SDF-1 mRNA levels were assayed in liver, spleen and marrow. SDF-1 protein levels were quantified in plasma and marrow and CXCR4 mRNA and protein levels were evaluated on stem/progenitor cells and megakaryocytes purified from the marrow. SDF-1 protein levels were also evaluated in plasma and in marrow biopsy specimens obtained from normal donors and PMF patients.Results-In Gata1 low mice, the plasma SDF-1 protein was 5-times higher than normal in younger animals. Furthermore, SDF-1 immuno-staining of marrow sections progressively increased with age. Similar abnormalities were observed in PMF patients. In fact, the plasma SDF-1 levels in PMF patients were significantly higher (by 2-fold) than normal (p<0.01) and SDF-1 immuno-staining of marrow biopsiy specimens demonstrated increased SDF-1 deposition in specific areas. In two of the patients, SDF-1 deposition was normalized by curative therapy with allogenic stem cell transplantation. Similarly to what already has been reported for PMF patients, the marrow from Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Gata1 low mice contained fewer CXCR4 pos CD117 pos cells and these cells expressed low levels of CXCR4 mRNA and protein. NIH Public AccessConclusion-Similar abnormalities in the SDF-1/CXCR4 axis are observed in PMF patients and in the Gata1 low mice model of myelofibrosis. We suggest that these abnormalities contribute to the increased stem/progenitor cell trafficking observed in this mouse model as well as patients with PMF.

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“…CXCR4 is widely expressed on hematopoietic cells, including stem cells, B cells, subsets of T cells, monocytes and neutrophils. It is known to fulfill an important role in hematopoiesis and organogenesis [1,2]. Moreover, CXCR4 has been studied in detail as coreceptor for HIV infection of T cells [3].…”

Section: Introductionmentioning

confidence: 99%

Post‐translational and cell type‐specific regulation of CXCR4 expression by cytokines

Brühl¹,

Cohen²,

Linder³

et al. 2003

Eur J Immunol

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We have investigated the regulation and function of the chemokine receptor CXCR4 on neutrophils. CXCR4 is hardly detectable on neutrophils in the peripheral blood. However, overnight culture strongly up-regulates CXCR4 expression on the cell surface. The functional activity of CXCR4 on cultured neutrophils was confirmed by stromal cell-derived factor (SDF)-induced migration and up-regulation of the integrins CD11b and CD11c. CXCR4 surface expression on neutrophils but not on lymphocytes and monocytes is rapidly downregulated after stimulation with TNF- § and IFN-+ , resulting in significantly decreased SDFinduced functional responses of neutrophils. In contrast to surface expression, CXCR4 mRNA expression was several-fold increased in cytokine-stimulated neutrophils, suggesting a post-translational regulation. By confocal microscopy we demonstrate that CXCR4 is internalized after stimulation with TNF- § and IFN-+ . b he down-modulation of CXCR4 surface expression in response to TNF- § and IFN-+ was fully reversible after cytokine removal. Further, CXCR4 down-modulation could be completely blocked by hypertonic sucrose and significantly reduced by chlorpromazine indicating the involvement of clathrin-coated pits. Internalization of CXCR4 by cytokines in a cell type-specific manner is a novel and functionally important mechanism of chemokine receptor regulation.

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Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development

Cited by 2,305 publications

References 30 publications

CXCR4/CXCL12 expression and signalling in kidney cancer

CXCR4/CXCL12 expression and signalling in kidney cancer

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Post‐translational and cell type‐specific regulation of CXCR4 expression by cytokines

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